Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release

Abstract

SummaryEffector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of “homing” receptors acquired by memory T cells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs T cell cardiotropism, which was associated with a specialized homing “signature” (c-Met+CCR4+CXCR3+). c-Met signals facilitated T cell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic T cell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during T cell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive T cells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies.

Another TLO in the Wall: Education and Control of T Cells in Atherosclerotic Arteries

“…Taken together, the results presented by Komarowska et al (2015) introduce a new paradigm for cardiac T cell tropism. In addition, the data are exciting because they raise the potential to alter tissuetropism of T cells that might modulate T cell-mediated pathology in the heartand relevant therapeutic compounds are already available.…”

HGF Guides T Cells into the Heart

“…In this issue of Immunity, Komarowska et al (2015) describe an autocrine loop that is initiated by cardiac-expressed hepatocyte growth factor to direct T cells into the heart during inflammation and cardiac transplant rejection.…”

“…Do tissue-derived factors induce specific sets of adhesion factors on T cells? In this issue of Immunity, Komarowska et al (2015) set out to address this experimentally, by investigating the role of hepatocyte growth factor (HGF) in T cell homing to the heart. Although it has been proposed previously that the chemokine receptors CXCR3 (and its ligand CXCL10) as well as CCR4 are contributing to T cell accumulation during heart transplantation (Hancock et al, 2001; Hü ser et al, 2005), it was unknown how the myocardium imprints cardiotropism during priming and differentiation of heart-specific T cells and whether such imprinting would take place in inflamed tissue or the draining lymph nodes.…”

“…Although it has been proposed previously that the chemokine receptors CXCR3 (and its ligand CXCL10) as well as CCR4 are contributing to T cell accumulation during heart transplantation (Hancock et al, 2001; Hü ser et al, 2005), it was unknown how the myocardium imprints cardiotropism during priming and differentiation of heart-specific T cells and whether such imprinting would take place in inflamed tissue or the draining lymph nodes. Findings from Komarowska et al (2015) suggest that HGF might be a master regulator of T cell cardiotropism.…”

“…The centerpiece of Komarowska et al (2015)'s study is a series of in vitro and in vivo experiments, in which a 7-day treatment with HGF in parallel with strong induction of TCR signaling via anti-CD3 and anti-CD28 stimulation enhanced responsiveness to the chemokines CXCL10 and CCL22 in migration assays in vitro, as well as directing cells to the peritoneal cavity in mice. These effects were dependent on binding of HGF to its receptor c-Met and induction of an intracellular signaling cascade involving Akt and STAT3 engagement.…”